Two specific areas with particular relevance to this project arescreening for the impact of metabolic signals and metabolic disease on hepatic expression of microRNAs, and the role of NRs and their targets in adverse drug reactions. This project is based on two general hypotheses: 1) Micro RNA expression is altered in response to nuclear receptor activation and other metabolic signals in the liver, allowing non-proliferative hepatocytes to alter their function over time. 2) The induction of hepatotoxicity in adverse drug reactions is associated with large scale alterations in expression of NRs, their coregulators and downstream metabolic targets, and distinct classes of hepatotoxic agents elicit distinct responses. We will test both hypotheses by leveraging the ongoing high throughput QPCR screening technologies developed by this Strand in the initial Phase of the NURSA project.